Theophylline (1,3-dimethyl xanthine) and related natural materials are used pharmacologically because of their activities on the central nervous system and the heart circulation function. Theophylline has an outstanding action in status asthmaticus and bronchial asthma. The water solubility which is only slight and consequently the slow resorption can be improved substantially by converting it into suitable water soluble derivatives.
The dihydroxypropyltheophylline [1,3-dimethyl-7-(.alpha., -dihydrohydroxpropyl)-xanthine] represents such a water soluble derivative. Its production is described e.g. by P. V. Maney et al in J. Amer. Pharm. Assoc. Vol. 35 pages 266-272 (1946) through reaction of theophylline with 3-chloro-1,2-dihydroxypropane (glycerine- .alpha.-monochlorohydrin) in the presence of an equivalent amount of aqueous sodium hydroxide. Several additional publications likewise describe the reaction of theophylline and glycerin-.alpha.-monochlorohydrin in the presence of KOH or NaOH (F. F. Auslander, Sci. Pharm. Proc. 25th, 1965, 1, 75-7; Jones U.S. Pat. No. 2,575,344; M. Samejima, Yakugarku Zasski Vol. 80 pages 1706-1723 (1960); see also Chem. Abst. Vol. 54 page 11648g and Chem. Abst. Vol. 55 page 10439i). D. Ishay recommends the reaction of theophylline with KOH in water with subsequent evaporation to dryness. Subsequently there takes place the addition of glycerine-.alpha.-monochlorohydrin and methanol. Yield 78% of melting point 155.degree. to 158.degree. C. (J. Chem. Soc. (London), page 3975 (1956)).
Most of the processes mentioned operate in aqueous medium with subsequent evaporation and recrystallization from methanol. Above all the disadvantage is the large amount of energy required which is due to the high vaporization enthalpy of water, as well as the accumulation of sodium chloride (0.230 kg/kg of dihydroxypropyl theophylline), which must be carefully and quantitatively separated from the reaction product.
A substantial improvement of the process results from the replacement of glycerine-.alpha.-monochlorohydrin by glycidol since in this case it is possible to work with small amounts of catalytically acting materials, the separation of large amounts of NaCL thus is eliminated. Besides it is possible to carry out the reaction in suitable solvents.
In Arch. Pharmaz. Ber. dt. pharmz. Ges. 292/64, 234 (1939) H. J. Roth reports on the reaction of theophylline and theobromine with 1,2-epoxides and employs as catalysts among others pyridine bases. The preferred solvent is n-propanol. In repeating these directions on a large scale it has been shown that a strong coloration of the reaction solution occurs through the pyridine, which coloration can only be eliminated by large amounts of activated carbon and furthermore the content of pyridine is very high (10% based on the theophylline employed). This leads to increased expense for apparatus in the purification of the mother liquors.
Besides the preparation obtained itself is of unsatisfactory purity after two recrystallizations (Roth gives a melting point of 154.degree. to 155.degree. C. ) and the yield is not satisfactory, about 60% of theory based on theophylline.
The object of the invention is to develop a process for the production of dihydroxypropyltheophylline using glycidol and theophylline in which the reaction product not only is obtained in good yields but also in high purity.